title: Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1β by suppressing AMP-activated protein kinase (AMPK) activation.
abstract: OBJECTIVE
  The mechanisms involved in the beneficial effects of fenofibrate on the development and progression of diabetic macular oedema (DMO) remain to be elucidated. To shed light on this issue we have explored the effect of fenofibric acid on the barrier function of human retinal pigment epithelium (RPE) cells.
  
  
  METHODS
  ARPE-19 cells (a human RPE line) were cultured for 18 days under standard conditions and under conditions leading to the disruption of the monolayer (D-glucose, 25 mmol/l, with IL-1β, 10 ng/ml, added at days 16 and 17). Fenofibric acid, 25 μmol/l and 100 μmol/l, was added on the last 3 days of the experiment (one application/day). RPE cell permeability was evaluated by measuring apical-basolateral movements of FITC-dextran (40 kDa). The production of tight junction proteins and AMP-activated protein kinase (AMPK) phosphorylation was assessed by western blot. Immunohistochemical studies of tight junction proteins and small interfering RNA transfection to AMPK were also performed in ARPE-19 monolayers.
  
  
  RESULTS
  Treatment of ARPE-19 cells with fenofibric acid significantly reduced the increment of permeability and the breakdown of the ARPE-19 cell monolayer induced by D-glucose, 25 mmol/l, and IL-1β, 10 ng/ml, in a dose-dependent manner. This effect was unrelated to changes in the content of tight junction proteins. Fenofibric acid prevented the activation of AMPK induced by IL-1β and the hyperpermeability induced by IL-1β was blocked by silencing AMPK.
  
  
  CONCLUSIONS
  Disruption of RPE induced by IL-1β is prevented by fenofibric acid through its ability to suppress AMPK activation. This mechanism could be involved in the beneficial effects of fenofibrate on DMO development.
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Villarroel
authors.forename: M
authors.initials: M
authors.lastname: Garcia-Ramírez
authors.forename: L
authors.initials: L
authors.lastname: Corraliza
authors.forename: C
authors.initials: C
authors.lastname: Hernández
authors.forename: R
authors.initials: R
authors.lastname: Simó
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D001692:Biological Transport / Q000502:physiology; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D003911:Dextrans / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008269:Macular Edema / Q000378:metabolism / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
chemical_list: D003911:Dextrans; D000960:Hypolipidemic Agents; D053583:Interleukin-1beta; C015219:fluorescein isothiocyanate dextran; C006012:fenofibric acid; D055372:AMP-Activated Protein Kinases; D016650:Fluorescein-5-isothiocyanate; D005947:Glucose; D011345:Fenofibrate